2, University of Colorado Boulder, Boulder, Colorado, United States
3, University of Colorado Boulder, Boulder, Colorado, United States
4, University of Colorado Boulder, Boulder, Colorado, United States
Hydrogels have shown tremendous potential in providing initial mechanical support to encapsulated cells during the process of tissue regeneration. Specifically, active hydrogels that respond to biological stimuli are found to be highly effective in enabling tissue growth by relaxation, degradation, etc. Once cells are encapsulated, the hydrogel can be designed to degrade and allow the transport of large extra-cellular matrix that matures into newly regenerated cartilage tissue. One of the toughest challenges here is programming hydrogel degradation for optimum growth conditions. For instance, hydrogel degradation that is too fast can result in complete loss of mechanical integrity whereas if it is too slow, it can deter growth. Understanding the physics that drive the processes of degradation and growth is, therefore, crucial in developing models that will help transition degradable hydrogels from the lab to the clinics. Supported by experiments and models, a key finding is that successful tissue growth occurs when there is a smooth transfer of mechanical properties from hydrogel to the new tissue. This can be achieved by: (a) matrix deposition with localized degradation and, (b) ensuring overall structural connectivity of the composite gel and neo-tissue. Localized degradation is possible with smart hydrogels whose bonds are designed to be sensitive to enzymes released from cells. This restricts transport of the extra-cellular matrix to the immediate vicinity of the cells where the hydrogel has degraded. The spatio-temporal behavior of hydrogel degradation and matrix deposition depend on the hydrogel properties and, often complex, cell behavior. Therefore, we have developed scaling laws that quantify these processes and potentially help tuning degradation. This microscale behavior is then transformed to predict the macroscopic evolution of mechanical properties based on the mechanics of composites. To ensure structural connectivity, we show that the presence of spatially well-connected and dense cell clusters is ideal. This is because the cell clusters create internal percolating tissue networks as the hydrogel degrades locally. The contribution of this work is an important step towards developing reliable design tools that help tune smart bio-responsive hydrogels for cartilage regeneration.